Carbon-ion radiotherapy—basic and clinical studiesJun 25, 2010 · Carbon-ion...

Carbon-ion Radiotherapy—Basic and Clinical Studies—

Koichi Ando, Gunma University, Maebashi, Japan

Abstract

Radiotherapy using charged and/or high-LET particles has a long history, starting with proton

beams. In vitro data clarify that RBE (Relative Biological Effectiveness) increases with LET up to

approximately 150 keV/μm for carbon-12 and neon-20 ions. In vivo studies show that tumor control probabilities after single doses of gamma rays shift to higher doses when tumors were

irradiated with 5-fractionated doses, while such a shift is not observed for carbon ions, and that

tumor reoxygenation is accelerated after carbon ions compared to γ-rays. The RBE for tumor control is greater than that for the skin response when fibrosarcoma and skin of mice are irradiated

with 3-5 dose fractions of 290 MeV/u carbon ions. Experimental results of secondary tumors

induced by carbon ions are included. Clinical results for various malignancies are also presented

here.

1. Introduction

Radiotherapy using charged and/or high-LET particles has a long history, starting with proton

beams. Ion beams “heavier” than protons, such as carbon, neon, silicon and argon were tried in

Phase I clinical trials, but the only heavy ion beams currently in use for radiotherapy are carbon.

The radiation quality of particle beams is different from conventional photons, and therefore

biological effects of high-LET irradiation have drawn the scientific interests of quite a few

scientists in both basic and clinical fields. After the closure of the Bevalac accelerator complex in

Berkeley, California that was used for the heavier- ion trials, hadrontherapy with carbon beams

was undertaken both in Japan and in Germany to continue the research.

Full-scale clinical studies with carbon ion therapy started in 1994 at the NIRS (National Institute

of Radiological Sciences) in Chiba, Japan using the HIMAC (Heavy–ion Medical Accelerator in

Chiba) synchrotron, and clinical trials with carbon at the GSI (Helmholtzzentrum für

Schwerionenforschung GmbH) in Darmstadt, Germany followed. Until 2009, almost 4000

patients have been treated by NIRS and 400 patients by GSI with extremely good results.

Encouraged by these results, other facilities also started carbon-ion therapy or construction of

Carbon-ion radiotherapy—basic and clinical studies. Ando K. https://three.jsc.nasa.gov/articles/AndoCarbonIonTherapy62510.pdf. Date posted: 06-25-2010.

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particle accelerators for radiotherapy; Hyogo Ion Beam Medical Center, Japan and the Institute of

Modern Physics, China started carbon-ion therapy in 2002 and 2006, respectively. The

Heidelberg Ion Beam Therapy Center (HIT) in Germany will start proton/carbon ion therapy in

2010 while the following four synchrotrons are currently under construction: Gunma University

Heavy Ion Medical Center at Maebashi in Japan, CNAO (Italian hadrontherapy center) at Pavia in

Italy, and two new facilities in Germany, the Kooperative Ionen Therapie Zentrum at Marburg and

NRock North European Radiooncological Center at Kiel.

2. Experimental studies of carbon-ion beams

In vitro data

The relationship between LET and RBE has been extensively studied using in vitro cultured cell

lines (Furusawa 2000). Figure 1 shows RBE values at a 10% survival fraction for human salivary

gland tumor cells (HSG) after single irradiation with helium-3, carbon-12 or neon-20. RBE

increases with LET up to approximately 150 keV/μm for carbon-12 and neon-20 ions. Helium ions show a more rapid increase of RBE with increasing LET than other ions. The oxygen

enhancement ratio (OER) for cell kill is approximately 3 for photons, and is reduced when LET

increases (Fig.2). OER becomes small when LET increases to 60 keV/μm and approaches unity at

500 keV/μm. With increasing LET, helium ions again show a more rapid decrease of OER than heavier ions.


Fig.1

Fig.2

Cytogenetic damage after carbon-ion beams has been studied with primary cultures of human

cells (Suzuki 2006). Six primary culture biopsies were obtained from 6 patients with carcinoma of

the cervix before starting radiotherapy, and cells at passage 4 were irradiated in vitro with X rays


[specify energy] or carbon ions. A good correlation between cell killing and excess chromatin

fragments (using the premature chromosome condensation technique) was observed for the 6

different cell cultures (Fig.3)

Fig.3

In vivo data

Tumor control probabilities (TCP) after single and fractionated irradiation with carbon ions were

studied for a murine transplantable tumor (Fig.4) (Ando, unpublished data) . TCP after single

doses of gamma rays shift to higher doses when tumors were irradiated with 5-fractionated doses,

while such shift is not observed for carbon ions. This observation has led to hypofractionation of

carbon radiotherapy with fewer treatments delivered over a short time course (Miyamoto T 2007).

Fig.4

0

20

40

60

80

100

0 20 40 60 80 100 120 140 160

P.Fig.1-041108

1C1γ5C5γ

Tum

or C

ontr

ol P

roba

bilit

y(%

)

Physical Dose (Gy)

Tumor Control Probabilities after Single and 5-dailyIrradiation with Carbon ions

NFSa/C3H

290MeV/u c-126CM SOBP 74keV/μm


Reoxygenation

Tumor oxygen status changes after irradiation so that reoxygenation takes place during

fractionated irradiation. Here tumor growth delay is measured after irradiation (Fig.5) (Ando,

unpublished data) .

Fig.5

Tumor reoxygenation is measured by a method that involves an initial irradiation, which is

followed by a second irradiation under conditions of either intact or clamped blood supply. When

the tumor growth delay is longer for the intact than for the clamped blood supply, the tumor is

reoxygenated.

100

1000

10 4

0 5 10 15 20 25 30 35 40

Fig.2.H60-2 74keV GD/980409-2

0Gy 5Gy10Gy15Gy20Gy25Gy30Gy

Tum

or V

olum

e (m

m3)

Days after Irradiation

LET 74keV/μm

tumor size 　7mmφ

200

300

500

2000

3000

5000

290 Mev/u Carbon-12 6cm SOBP


As seen in figure 6, tumor reoxygenation is accelerated after carbon ions compared to γ-rays (Ando 1999).

Fig.6

One explanation for the acceleration of tumor reoxygenation with carbon ions may be the random

killing of both oxic and hypoxic cells with carbon ions allowing more reoxygenation (Fig.7).

Fig.7


Normal tissue damage

Mouse jejunum crypt survivals have been studied after irradiation with carbon ions at NIRS and

GSI (Fig.8) (Uzawa 2009). Survival curves for the 2 institutions are similar at 3 different positions

within a 6-CM SOBP (Spread-Out Bragg peak), indicating beam spreading methods at each

facility do not change the biological effectiveness of carbon ions.

Fig.8


The therapeutic gain of carbon ions has been studied by comparing RBE (Relative Biological

Effectiveness) between tumor and skin. Figure 9 shows

Fig.9

that the RBE for tumor control is greater than that for the skin response when both tissues are

irradiated with 3-5 dose fractions of the SOBP but not the entrance plateau of 290 MeV/u carbon

ions (Ando2005 ).

The risk of secondary tumors induced by carbon-ion beams has also been studied in vitro and in

vivo (Imaoka 2007). Secondary mammary carcinomas are more prevalent in Sprague-Dawley rats


irradiated with 290 MeV/u carbon ions (LET 40–90 keV/μm) (Fig.10).

Fig.10


The transformation induction for high-energy (therefore low LET) carbon ions is comparable to

that for photons, whereas for carbon ions of lower energies, the probability of transformation in a

single cell is greater than that for photons (Fig.11) (Bettega 2009). The LET values for the

accelerated carbon ions shown in figure 11 are 13.5 keV/μm (270 MeV/u), 26.4 keV/μm (100

MeV/u) and 149 keV/μm (11.4 MeV/u).

Fig.11

3. Clinical studies

At the NIRS, carbon-ion radiotherapy has been completed using 50 protocols on over 4000

patients with a variety of tumors. Carbon-ion radiotherapy is effective in such regions as the head

and neck, skull base, lung, liver, prostate, bone and soft tissues, and pelvic recurrence of rectal

cancer, as well as for histological types including adenocarcinoma, adenoid cystic carcinoma,

malignant melanoma and various types of sarcomas. The number of irradiation sessions per

patient and the overall treatment time has been reduced compared to conventional radiotherapy

and averages 13 fractions spread over approximately three weeks. A new therapy facility is under


construction at NIRS where rotatable gantry and spot-scanning will be used for carbon-ion

radiotherapy.

Treatment planning and dose prescription

The first preparatory procedure for Carbon-ion radiotherapy is the fabrication of custom-made

immobilization devices for each patient. Planning-CT scans are taken with the patients wearing

these devices. The CT image data obtained in this manner are transferred to the treatment planning

system, in which delineation of target volumes is made by physicians using CT images or fusion

images consisting of CT, MRI and PET images. Patient-specific irradiation parameters are then

determined for designing the bolus and collimators for selective irradiation of the tumor strictly in

accordance with these parameters. Radiation delivery is performed by the passive method using

modulators, collimators and compensators. If the patient requires respiratory-gated irradiation,

respiration-synchronizing devices are also used for them at the time of the CT scans.

The dose is indicated in GyE, calculated by multiplying the physical carbon dose (Gy) by RBE so

as to permit a comparison with photon beams: GyE = physical dose x RBE. Irrespective of the

length of the SOBP, the RBE of the carbon-ion beams used for radiotherapy is 3.0 at the distal part

of the SOBP. This value is identical with the RBE previously used in fast neutron radiotherapy at

NIRS.


Number of patients

The number of patients treated to date with carbon ions varies depending on tumor location.

Prostate tumor is the most frequently treated condition, followed by lung, head and neck, and

bone/soft tissue tumors (Fig.12) (Tsujii 2008).

Fig.12

Clinical outcome

The clinical outcome of carbon radiotherapy varies, depending on tumor sites and protocols.

Table 1 and 2 show the summary of survival rates of patients (Tsujii 2007). In short, prostate

tumors show more than 90% 5-year survivals. Uterus cervix tumors range from 40% to 60%,

bone/soft tissue sarcomas 40% to 80 %, head and neck 30% to 70 %, tumors at skull

base/cervical spine 90%, lung tumors 20% to 50% and liver tumor 30% to 70 %.


Table 1 Results of carbon Ion Radiotherapy at NIRS (Treatment Period：6.1994~2.2006) (Part 1)


Table 2 Results of carbon Ion Radiotherapy at NIRS (Treatment Period：6.1994~2.2006) (Part 2)


Figure 13 shows local control rates for head and neck patients after carbon-ion radiotherapy

(Tsujii 2008). Many tumors respond well to carbon-ion radiotherapy, while squamous cell

carcinomas show only moderate responses.

Fig.13

Summary

Described here is a brief review of carbon ion radiotherapy for physicians and scientists with some

background in the field of radiation therapy. Readers could find a detailed review article on

biological effects of high LET radiation (Ando and Kase (2009)

References

Ando K et al. (1999) Accelerated reoxygenation of a murine fibrosarcoma after carbon-ion

radiation. Int J Radiat Biol. 75(4):505-12.

Ando K et al. (2005) Biological gain of carbon-ion radiotherapy for the early response of tumor

growth delay and against early response of skin reaction in mice. J Radiat Res 46(1):51-57.

Ando K and Kase Y (2009) Biological characteristics of carbon-ion therapy. Int J Radiat Biol.

85(9):715-28.


Bettega D et al. (2009) Neoplastic transformation induced by carbon ions, Int J Radiat Oncol

Biol Phys. 73(3):861-868.

Furusawa Y et al. (2000) Inactivation of aerobic and hypoxic cells from three different cell lines

by accelerated (3)He-, (12)C- and (20)Ne-ion beams. Radiat Res.154(5):485-96

Imaoka et al. (2007) High relative biologic effectiveness of carbon ion radiation on induction of

rat mammary carcinoma and its lack of H-ras and Tp53 mutations. Int J Radiat Oncol Biol Phys.

69(1):194-203.

Miyamoto T et al. (2007) Curative treatment of Stage I non-small-cell lung cancer with carbon

ion beams using a hypofractionated regimen. Int J Radiat Oncol Biol Phys. 67(3):750-8.

Suzuki M et al. (2006) The PCC assay can be used to predict radiosensitivity in biopsy cultures

irradiated with different types of radiation. Oncol Rep. 16(6):1293-1299

Tsujii H et al. (2007) Clinical Results of Carbon Ion Radiotherapy at NIRS. J Radiat Res 48

Suppl A:A1-A13.

Tsujii H et al. Clinical advantages of carbon-ion radiotherapy. New Journal of Physics 10

(2008) 075009

Uzawa et al. (2009) Comparison of biological effectiveness of carbon-ion beams in Japan and

Germany. Int J Radiat Oncol Biol Phys. 73(5):1545-1551


Carbon-ion radiotherapy—basic and clinical studiesJun 25, 2010 · Carbon-ion...

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